1. Field of Invention
This invention relates to cellular electrical measurements in general, for animals, including humans, and neuron electrical measurements in particular.
2. Definition of Terms
To assert. In digital electronics it means to make a wire on or off, as needed, or a set of wires to be in any combination on and off, as needed. In this context “on” an “off” generally mean one of the two possibilities of a binary representation, as on=5V, off=0V, on=magnetic field up, off=magnetic field down, on=light, off=dark, etc.
B/H/D after a number, or in subindex, stands for binary/hexadecimal (hex)/decimal number representation. For example: 1010B=0AH=10D
Bus. A set of wires grouped according to its function. For example, the address bus is the set of wires which carries the address value for something, the data bus is the set of wires which carries the data, or numerical value for something.
Demultiplexer. A type of electronic switch with a single input and a plurality of outputs, also with a number of binary inputs capable of creating a binary address which can select which of the outputs will be connected to the single input (cf. multiplexer). The device of our invention uses a demultiplexer capable of also latching the output selection, that is, a demultiplexer that maintain the connection between the single input and the selected output even after the address is out from its address port (it latches), or even if the address changes to another value.
Integrated circuit. As used herein, the term “integrated circuit” refers to a small-scale, electronic device densely packaged with more than one integrated, electrical component. The components are manufactured on the surface of semiconductor material. There are various scales of integrated circuits that are classified based on the number of components per surface area of the semiconductor material, including small-scale integration (SSI), medium-scale integration (MSI), large-scale integration (LSI), very large-scale integration (VLSI), ultra large-scale integration (ULSI)
Latch. A term used in digital electronics meaning the capability to keep some particular configuration, or output, or logic, or selection, even after the selecting source, etc., is no longer active, or even if the selecting source is changed to a different value. Another way to look at it is that a latched device has memory to keep a configuration when instructed to do so. A standard wall light switch is an example of a latch because it keeps the last state it was set by a human being, either on or off.
Measuring tip. The very tip of the measuring wire, sometimes referred as electrode in current art, made of metal or some other electrically conducting material. In current art devices the measuring tip is generally at the end of a thin, stiff wire, typically 100 micrometers diameter, separated by 100 micrometers, or more, while in our invention the measuring tip is a metallic area as small as a few micrometers, typically 5 micrometers but can be less or more according to the need, separated by as little as 5 micrometers, at the surface of the device of our invention. Current art is capable of manufacturing measuring tips for our invention that are less than one micrometer in diameter, and the shape is not necessarily circular.
Multiplexer (MUX) a type of electronic switch with a plurality of inputs and one single output, also with a number of binary inputs capable of creating a binary address which can select which of the inputs will be connected to the single output. (cf. Demultiplex).
Neural sensor. As used herein, the term “neural sensor” means an implantable device for sensing neural signals. Examples of neural sensors include microwire electrode arrays, optical sensors, microwires, magnetic field detectors, chemical sensors, and other suitable neural sensors which are known to those of skill in the art upon consideration of the present disclosure.
Picafina. A supporting structure used by the main embodiment of our invention, generally similar to the devices used in Deep Brain Stimulation but potentially with far more tips or electrodes than DBS devices, which is strong enough to allow it to be inserted in the brain or other body structures, and which contains the necessary wires for connecting the measuring tips and the address decoders with the controlling and measuring instruments. For use human animals, he dimension of a type I picafina is approximately the size of a wide drinking straw (5 mm.), its length being the necessary to reach the desired depth in the body. For smaller animals (as a mouse), the picafinas would be accordingly smaller, both in diameter and length, while for larger animals (as a whale or an elephant), the picafinas would be accordingly larger.
3. Short Introduction to the Art
It is well established that the neuron signals are electrically propagating signals. The roots of this fact can be traced at least to the Italian Luigi Galvani as early as 1771 with his famous frog's leg experiment.
This neuronal (electrical) traffic travels in both directions, from either the brain or intermediate neurons to the muscles or other body parts, or from sensory organs (skin, taste buds, vision rods and cones, etc.) to either other intermediate neurons or the brain. Measuring these signals is of importance for at least two reasons: such measurements may give us a clue of how the brain works; they may also help us to develop electrical actions on the nerves and on the brain to do things as to stop pain or to stop Parkinson's disease tremor or to stop epileptic seizures, etc. Accordingly, much effort has been put into devices to measure the neuronal electrical activity. Eric Kandel (Kandel (2000)) gives a good overview of the current state of the art from the academic point-of-view, while Miguel Nicolelis (ed.) (Nicolelis (2008)) gives a current review of the electrodes measuring devices directly related to the our invention here disclosed.
Accordingly, to measure the neuronal electrical activity, several measuring electrodes, or probes, or measuring pads, or measuring tips, henceforth most often referred to as “measuring tips” or simply “tips” have been developed.
The single tips used in the early days of the art have given place to multiple tips, and the sizes of said tips is much smaller in current art. These multiple tips have a double objective. One is to make simultaneous measurements, both to collect more data, as well as to investigate the correlation between the firing of different neurons. A second objective is associated with the widely known difficulty of accurately positioning said tips with its distal end at the precise area of interest, at a precise position relative to any neuron, say, close to a synapse, or to a particular neuron. With multiple tips, one of them, by chance, may happen to be near one of the areas of interest, so supporting devices with several tens, or even over one hundred tips have been introduced. Yet, in spite of the recognized need of better adjustment of the measuring point, no real solution has been offered to this known problem: how to have a very large number of reading positions on the area studied, for example a brain (or a spinal cord, or some nerve bundle going to or from a finger, etc.). A device with more measuring tips, capable of measuring more points, and also points that are closer to each other is needed. Note also that the multi electrode arrays of current art cannot select a position a few micrometers near a particular position, but only the other electrode at the end of another wire, that, because it is separated by a supporting structure, can hardly be less than 100 micrometers away. It follows that current art can only make measurements at points which is too far for the small synapses that may measure just a few micrometers. The advantage, or even necessity, of having a larger number of electrical tips to serve as electrical measuring points is known in the community, yet, despite much interest and work devoted to it, no solution was ever proposed to this known problem. Indeed, given the picafina diameter limitations, there is an intrinsic limitation on the number of wires that can be carried inside it, which in turn sets a limit on the number of possible tips on its surface or so is accepted by current art. The small number of tips (electrical contacts) has been one of the recognized problems associated with the art, a problem which has never solved even though much effort has been put to its solution. This is a problem that has been crying for solution for a long time. This is the problem addressed and solved by our invention.
Our invention is a picafina with a much larger number of tips than the current art devices, potentially of the order of many thousand tips. Besides disclosing a device with such a larger number of tips, our invention discloses a method to bring out the voltage values, without which the small diameter of said picafinas would not allow such large numbers of tips to send out the measured values using dedicated wires, as dedicated wires to each tip would not fit inside current art picafinas which have to be as small as possible in order to minimize trauma to the animal.
4. Discussion of Prior Art
The measuring tips or electrodes, as it is said within the neurology community, or neuron measuring electrodes or tips, to be more precise, are in prior art made of small electrically conductive tips, physically attached to some supporting structure, which is usually small to be accommodated inside the body of a living animal (including humans). They can be viewed as neural sensors. This electrical measuring tip, or neural sensor, is connected as needed to some usually external measuring instrument (usually a voltmeter) after being amplified, this amplification often occurring still inside the animal at the probe location. The electric potential at the neuron site is of the order of microvolts to millivolts. Often the electrodes, or probe, or tip, or pad, are held by equipment to help the researcher or neurosurgeon to move the tip with micrometer precision, which is needed to position it in close vicinity to a neuron (Nicolelis (2008), ch 1, pgs 12-20)
The measuring tip has to be such that it can be placed substantially close to the intended neuron, usually of the order of a few micrometers or even a fraction of a micrometer distance. The measuring tip itself has to be of a size comparable with the physical size of the system that is producing the signals it is measuring, that is, of a size comparable with the size of a neuron, or else it will make contact with other nearby systems, measuring averages from several neurons at the same time. This means that the measuring tip has to have a size on the order of one to a few tens micrometers in diameter, if it is to measure an individual neuron. There are probes intended to measure a group of neurons, and these can be larger.
Examples of multi electrode arrays in current use can be seen at G. Lehew and M. A. L. Nicolelis “State-of-the-Art Microwire Array Design for Chronic Neural Recordings” in Nicolelis (2008) pg. 1, where there are descriptions and photos of multi electrode arrays from 8 up to 128 electrodes or tips. The problem with these electrodes is that they are on individual, separated supporting wires, one wire for each tip, which increase the trauma on the animal, and prevent the electrodes from being less than 100 micrometers separation from each other. Scott J. Cruikshank and Barry W. Connors (Cruikshank (2008)) and James F. A. Poulet and Carl C. H. Petersen (Poulet (2008)) also discuss the needs, problems and current state of the art of multi electrodes measuring devices.
Some of the current art devices are the electrode manufactured by Alpha Omega Engineering (http://www.alphaomega-eng.com/microelectrods/sma.asp) (Alpha Omega Engineering/PO Box 810/Nazareth Illit 17105/Israel/Tel 972-4-656-3327/Fax 972-4-657-4075/info@alphaomega-eng.com)
Many probes have several measuring tips, which allow concurrent measurements on several neurons. The multiplicity of tips also serves to adjust the exact point of measurement, because it is known to be difficult for the researcher (in a laboratory animal) or for the neurosurgeon (on a human patient) to position said measuring tip next to a particular neuron of such small dimensions. Ultimate measurement location is adjusted by selecting one or other (or several) of said tips or contacts. Tip selection is then made after insertion of the probe in the general area from which measurements are to be made, as the researcher, or the neurosurgeon, switch the measuring equipment from one tip to the next until, after having flipped through many tips that produce no signal or poor signal, he/she finds a tip that produces a good signal. There are also multi tips devices which allow each tip to be moved independently, usually forward and backwards only. Our invention offers an improvement on this change from one measuring tip to another, making it easier and more efficient. Our invention also allows the investigator or the neurosurgeon to make concurrent measurements on neurons closer together than previous art multi tip probes which have to be separated by the minimum distance of their supporting wires, which is of the order of 100 micrometers or more.
Irazoqui-Pastor (Irazoqui-Pastor (2008)) discloses an implantable device with multiple reading tips and a MUX (multiplexer), but he does not disclose a method and a means to have measuring tips that are very small and in very close proximity to each other (densely packed), in such a way as to cover a large area with selectable tips. In particular Irazoqui-Pastor does not disclose a system capable of combining the measuring tips together to make measuring areas of variable sizes, adjustable to the neuron size and location. And above all, Irazoqui-Pastor implicitly discloses an invention in which a large number of signal wires have to be brought to the MUX, a situation that forestalls a very large number of measuring tips in a small device. Nor did Irazoqui-Pastor disclosed a method to select a particular measuring tip then to keep it selected and to have a few selected together. Indeed, Irazoqui-Pastor disclosed the use of a MUX in the conventional way, which is in situations where space is not a problem. Because of these reasons, the invention disclosed by Irazoqui-Pastor fails to teach a method to allow a very large number of tips to be used, say, hundreds or thousands of tips, and accordingly, Irazoqui-Pastor does not mention the possibility of thousands of measuring tips.
Jenkins et al. (Jenkins (2006)) discloses a multiple tip system both for acquiring electrical signals and applying stimulation as well, but his invention is limited in that as disclosed, the number of measuring (or, stimulating) tips is limited, like all previous art electrodes, by the number of wires that can fit on the elongated body of the device. Superficially, Jenkins teachings is similar to mine, but without a very large number of individually addressable tips, the researcher cannot adjust precisely the location of measurement to be near one single neuron, and in this is the fundamental difference between his invention and mine. The need for a large number of contact tips has been recognized for a long time, and similar devices with multiple rings have been in use for Deep Brain Stimulation (DBS) (Medtronics (n/d)), but the constraint on the number of wires has kept the devices from advancing. Moreover, Jenkins failed to disclose the possibility of using the semiconductor manufacturing and printed circuit boards manufacturing techniques to achieve the smallest sized tips, what limits his tips to relatively large sizes.
Another example of modern prior-art devices is Donoghue et al. (Donoghue (2007)). His invention discloses a multi tip device, with each tip at the end of a small needle. Using this construction, the minimum separation of the tips is twice the size (diameter) of the supporting needle. Since the supporting needle can hardly be smaller than 50 micrometers, else it breaks, the distance between two reading electrodes is 100 micrometers minimum. Since 100 micrometers is much more than the size of a synapse in a typical brain neuron, it follows that this structure cannot adjust the measurement position with accuracies of the order of a fraction of the size of a neuron, as our invention can, and as it is needed.
Another examples of use of measuring devices are heart, muscle, pain carrying nerves, spinal cord etc.